The protective antigen (PA) of Bacillus anthracis plays a crucial role in the pathogenesis of anthrax. The fourth domain of PA (PA-D4) is responsible for initial binding to the cellular receptor ATR and thus PA-D4 is an attractive target for structure-based drug therapies. We hypothesize that peptides, peptoids, or small drug-like molecules that bind to PA-D4 will disrupt B. anthracis toxicity in vivo and that detailed structural and dynamic information will allow for optimization of these PA antagonists. The long-term goal of this research is to develop novel therapies against anthrax. The specific aims are: (1) the solution structure and the dynamic properties of B. anthracis PA-D4 will be determined by NMR spectroscopy; (2) the complementary approaches of phage display, in silico drug discovery, high throughput drug screening by NMR, and high throughput screening by pulsed mass spectrometry will be pursued to discover peptides and small drug-like compounds that bind to B. anthracis PA-D4; (3) peptides, peptoids, and drug-like compounds will be assayed for their ability to block B. anthracis PA-D4 binding to cells; (4) the PA-D4/peptide, PA-D4/peptoid and PA-D4/drug complexes will be characterized by biophysical techniques for future optimization of PA antagonists.